Process for the preparation of aniline-derived thyroid receptor ligands

ABSTRACT

Provided are processes for the synthesis of aniline derivatives, specifically certain aniline derivatives which have activity as thyroid receptor ligands.

This application claims the benefit of provisional application Ser. No.60/336,318 filed Nov. 2, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to processes for the synthesis of organicmolecules, specifically molecules that have activity as thyroid receptorligands.

While the essential role of thyroid hormones in regulating metabolism inhumans is well recognized, the discovery and development of new specificdrugs for improving the treatment of hyperthyroidism and hypothyroidismhas been slow. This has also limited the development of thyroid agonistsand antagonists for treatment of other important clinical indications,such as hypercholesterolemia, obesity and cardiac arrhythmias.

Thyroid hormones affect the metabolism of virtually every cell of thebody. At normal levels, these hormones maintain body weight, themetabolic rate, body temperature, and mood, and influence serum-lowdensity lipoprotein (LDL) levels. Thus, in hypothyroidism there isweight gain, high levels of LDL cholesterol, and depression. In excesswith hyperthyroidism, these hormones lead to weight loss,hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias,heart failure, muscle weakness, bone loss in postmenopausal women, andanxiety.

Thyroid hormones are currently used primarily as replacement therapy forpatients with hypothyroidism. Therapy with L-thyroxine returns metabolicfunctions to normal and can easily be monitored with routine serummeasurements of levels of thyroid-stimulating hormone (TSH), thyroxine(3,5,3′,5′-tetraiodo-L-thyronine, or T₄) and triiodothyronine(3,5,3′-triiodo-L-thyronine, or T₃). However, replacement therapy,particularly in older individuals, is limited by certain of thedeleterious effects of thyroid hormones.

In addition, some effects of thyroid hormones may be therapeuticallyuseful in non-thyroid disorders if adverse effects can be minimized oreliminated. These potentially useful influences include weightreduction, lowering of serum LDL levels, amelioration of depression andstimulation of bone formation. Prior attempts to utilize thyroidhormones pharmacologically to treat these disorders have been limited bymanifestations of hyperthyroidism, and in particular by cardiovasculartoxicity.

Development of specific and selective thyroid hormone receptor agonistscould lead to specific therapies for these common disorders whileavoiding the cardiovascular and other toxicities of native thyroidhormones. Tissue-selective thyroid hormone agonists may be obtained byselective tissue uptake or extrusion, topical or local delivery,targeting to cells through other ligands attached to the agonist andtargeting receptor subtypes. Thyroid hormone receptor agonists thatinteract selectively with the β-form of the thyroid hormone receptoroffer an especially attractive method for avoiding cardio-toxicity.

Thyroid hormone receptors (TRs) are, like other nuclear receptors,single polypeptide chains. The various receptor forms appear to beproducts of two different genes α and β. Further isoform differences aredue to the fact that differential RNA processing results in at least twoisoforms from each gene. The TRα₁, TRβ₁ and TRβ₂ isoforms bind thyroidhormone and act as ligand-regulated transcription factors. In adults,the TRβ₁ isoform is the most prevalent form in most tissues, especiallyin the liver and muscle. The TRα₁ isoform is prevalent in the pituitaryand other parts of the central nervous system, does not bind thyroidhormones, and acts in many contexts as a transcriptional repressor. TheTRα₁ isoform is also widely distributed, although its levels aregenerally lower than those of the TRβ₁ isoform. This isoform may beespecially important for development. Whereas many mutations in the TRβgene have been found and lead to the syndrome of generalized resistanceto thyroid hormone, mutations leading to impaired TRα function have notbeen found.

A growing body of data suggest that many or most effects of thyroidhormones on the heart, and in particular on the heart rate and rhythm,are mediated through the α-form of the TRα₁ isoform, whereas mostactions of the hormone such as on the liver, muscle and other tissuesare mediated more through the β-forms of the receptor. Thus, aTRβ-selective agonist might not elicit the cardiac rhythm and rateinfluences of the hormones but would elicit many other actions of thehormones. It is believed that the α-form of the receptor is the majordrive to heart rate for the following reasons:

1. tachycardia is very common in the syndrome of generalized resistanceto thyroid hormone in which there are defective TRβ-forms, and highcirculating levels of T₄ and T₃;

2. there was a tachycardia in the only described patient with a doubledeletion of the TRβ gene (Takeda et al., J. Clin. Endrocrinol. & Metab.1992, Vol. 74, p. 49);

3. a double knockout TRα gene (but not β-gene) in the mouse has a slowerpulse than control mice; and,

4. western blot analysis of human myocardial TRs show presence of theTRα₁, TRα₂ and TRβ₂ proteins, but not TRβ₁.

If these indications are correct, then a TRβ-selective agonist could beused to mimic a number of thyroid hormone actions, while having a lessereffect on the heart. Such a compound may be used for: (1) replacementtherapy in elderly subjects with hypothyroidism who are at risk forcardiovascular complications; (2) replacement therapy in elderlysubjects with subclinical hypothyroidism who are at risk forcardiovascular complications; (3) obesity; (4) hypercholesterolemia dueto elevations of plasma LDL levels; (5) depression; and, (6)osteoporosis in combination with a bone resorption inhibitor.

Thyroid receptor ligands of the formula I, below, have previously beensynthesized by several methods including the method summarized in SchemeA (See U.S. patent application Ser. No. 09/761,050, filed Jan. 16,2001.) The group G represents any group appropriate for protecting ahydroxyl moiety. The group Z represents a leaving group, such as ahalogen. Examples of appropriate protecting groups G can be found, forexample, in T. W. Greene & P. G. M. Wuts, “Protecting Groups in OrganicSynthesis”, 3rd Edition, Wiley, 1999.

This route is not optimal, however, due to the exothermicity of theformation of the iodonium triflate salt which is an unisolatedintermediate in the synthesis depicted in Scheme A. In addition, theisolated, bis-phenyl iodonium salt is an intractable gummy solid at roomtemperature, and the yield of the formation reaction is unpredictable.Further, the coupling reaction to form the mixed ether from the iodoniumsalt is not well adapted to commercial practice, because it takes placeover an extended period of time, it requires unusual provisions toexclude light, and its yield is also unpredictable.

Accordingly, there is a need for improved processes for the preparationof thyroid receptor ligands, especially for processes that improve uponthe safety and economic feasibility of the processes known in the art.

SUMMARY OF THE INVENTION

The present invention relates to the synthesis of compounds that haveactivity as thyroid receptor ligands, specifically compounds of formulaI

wherein:

R¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6carbons, or a cycloalkyl group of 3 to 7 carbons;

R² and R³ are the same or different and represent hydrogen, halogen, analkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons,at least one of R² and R³ being other than hydrogen;

R⁴ represents hydrogen or a lower alkyl group;

R⁵ represents a carboxylic acid or an alkyl ester thereof; and

Y represents —(CH₂)_(n)— where n is an integer from 1 to 5, or a cis- ortrans-ethylene group —CH—CH—;

and all stereoisomers thereof, prodrug esters thereof, andpharmaceutically acceptable salts thereof.

Compounds of formula I may be synthesized by reacting a compound offormula III with a phenol of formula A, wherein G is a protecting group,in the presence of a base to produce a compound of formula IV, whereinR¹, R², R³, and R⁴ are as defined above;

deprotecting the compound of formula IV to form a compound of formula V;

reducing the compound of formula V to produce a compound of formula VI;

reacting the compound of formula VI with a compound of the formulaXC(O)YR⁵, wherein X represents OH or a halogen and R⁵ is a carboxylicacid alkyl ester, in the presence of a base, to produce a compound offormula I wherein R⁵ is a carboxylic acid alkyl ester; and

optionally de-esterifying the compound of formula I wherein R⁵ is acarboxylic acid alkyl ester to produce a compound of formula I whereinR⁵ is a carboxylic acid.

Also provided by the present invention are compounds that are novelstarting materials of the above process having the formulae IIA and IIIA

wherein

R² and R³ independently represent bromo, chloro, or methyl;

R⁴ represents hydrogen or methyl; and

L represents mesyl, tosyl, p-nitrobenzenesulfonyl, trihaloacetate, ortriflate.

The present invention also provides compounds of the formulae A, A-I,and A-II

wherein M is a metal and G and R¹ are as defined above. In compounds offormula A, however, when G is a methyl group, R¹ is not a bromo, chloro,iodo, t-butyl, cyclohexyl, cyclopentyl, or isopropyl group.

Also provided by the present invention is a process for synthesizing aphenol of formula A, above, by reacting an aldehyde of formula A-I,above, with M⁺HSO₃ ⁻ wherein M is a metal to form a sulfonate of formulaA-II, above. The sulfonate of formula A-II is reacted with an oxidant inthe presence of a proton source to form the phenol of formula A.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the results of a temperature vs. time study of theformation reaction of the iodonium triflate salt of the comparativeexample.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

The term “thyroid receptor ligand” as used herein, is intended to coverany moiety which binds to a thyroid receptor. The ligand may act as anagonist, an antagonist, a partial agonist or a partial antagonist.Another term for “thyroid receptor ligand” is “thyromimetic”.

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or as part of another group includes both straightand branched chain hydrocarbons, containing 1 to 12 carbons (in the caseof alkyl or alk), in the normal chain, preferably 1 to 4 carbons, suchas methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. Each alkyl groupmay be optionally substituted with 1 to 4 substituents which may includealkyl, alkenyl, alkynyl, aryl, cycloalkyl, halogen, heteroaryl, hydroxy,cyano, nitro, amino and/or carboxyl or alkyl ester thereof.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl including1-naphthyl and 2-naphthyl) and may be optionally substituted throughavailable carbon atoms with 1, 2, or 3 groups selected from hydrogen,halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano and/or carboxylor an alkyl ester thereof.

The term “heteroaryl” or “heteroaromatic moiety” as used herein alone oras a part of another group refers to a 5- or 6-membered aromatic ringwhich includes 1, 2, 3, or 4 heteroatoms, one of which must be anitrogen atom; the other heteroatoms when present may be nitrogen,oxygen or sulfur, and such rings may be fused to another aryl orheteroaryl ring. The heteroaryl groups may include one or more N-oxides.The heteroaryl group may optionally include 1 to 4 substituents such asaryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, cyano, nitro, aminoand/or carboxyl, or an alkyl ester thereof.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 12 carbons, preferably 2 to 5 carbons,in the normal chain, which include one to six double bonds in the normalchain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-peritenyl,3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like,which may be substituted in the same manner as that described for alkylgroups.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or as part of another group refers to straight orbranched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons,in the normal chain; which include one triple bond in the normal chain,such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl,2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl,3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like, which maybe substituted in the same manner as that described for alkyl groups.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes, saturated cyclic hydrocarbongroups or partially unsaturated (containing 1 or 2 double bonds) cyclichydrocarbon groups, containing one ring and a total of 3 to 7 carbons,preferably 3 to 6 carbons, forming the ring, which includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl andcyclohexenyl, which may be substituted in the same manner as thatdescribed for alkyl groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to fluorine, chlorine, bromine, and iodine, with chlorineor bromine being preferred.

The term “metal” as used herein refers to an element that can exist as apositive ion in solution. Suitable metals include alkali metals,transition metals, lanthanides, and actinides. Alkali metals arepreferred Lithium, sodium, and potassium are the most preferred metals.

As used herein, the term “about” means that amounts, sizes,formulations, parameters, and other quantities and characteristics arenot and need not be exact, but may be approximate and/or larger orsmaller, as desired, reflecting tolerances, conversion factors, roundingoff, measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such.

The divalent linking group represented by Y may be an alkylene group—(CH₂)_(n) — that includes 1 to 5 carbons in the normal chain, and mayalso include 1, 2, or 3 alkyl substituents.

Examples of (CH₂)_(n) groups include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂——CH₂CH₂C(CH₃)₂CH₂—,—CH₂CH₂CH(CH₂CH₃)CH₂——CH₂CH₂CH(CH₂CH₃)CH₂CH(CH₃)—,—C(CH₃)(CH₂CH₃)CH₂CH₂—, —CH(CH₃)—, —CH(CH₂CH₃)—,—CH(CH₃)CH₂CH(CH₂CH₃)CH₂—

Alternatively, Y may represent a cis- or trans-alkylene group—CH=CH—which may be substituted as described above.

The compounds of formula I may be present as salts, in particularpharmaceutically acceptable salts. If the compounds of formula I have,for example, at least one basic center, they can form acid additionsalts. These are formed, for example, with strong inorganic acids, suchas mineral acids, for example sulfuric acid, phosphoric acid or ahydrohalic acid, with strong organic carboxylic acids, such asalkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted orsubstituted, for example, by halogen, for example acetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulforiic acids, such as (C1-C4) alkyl or arylsulfonicacids which are unsubstituted or substituted, for example by halogen,for example methanesulfonic acid or p-toluenesulfonic acid.

Corresponding acid addition salts can also be formed having, if desired,an additional basic center. The compounds of formula I having at leastone acid group (for example COOH) can also form salts with bases.Suitable salts with bases are, for example, metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium ormagnesium salts, or salts with ammonia or an organic amine, such asmorpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di-, ortri-lower alkylamine, for example ethyl, t-butyl, diethyl, diisopropyl,triethyl, tributyl or dimethyl-propylamine, or a mono, di, or trihydroxylower alkylamine, for example mono, di or triethanolamine. Correspondinginternal salts may furthermore be formed. Salts which are unsuitable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free compounds of formula I or theirpharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of formula I which include a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate or nitrate.

Preferred salts of the compounds of formula I which include an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

Preferred compounds of formula I are those wherein

Y represents —(CH₂)_(n)— where n is 1 or 2;

R¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6carbons, or a cycloalkyl group of 3 to 7 carbons;

R² and R³ independently represent bromo, chloro, or methyl;

R⁴ represents hydrogen or methyl; and

R⁵ represents carboxyl.

More preferred compounds of formula I are those wherein

Y represents —(CH₂)_(n)— where n is 1;

R¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6carbons, or a cycloalkyl group of 3 to 7 carbons, most preferred beingisopropyl;

R² and R³ independently represent bromo or chloro;

R⁴ represents hydrogen or methyl; and

R⁵ represents carboxyl.

Compounds of formula I that can be prepared by the methods of theinvention include the following:

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-2-methyl-phenyl]-malonamicacid;

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-succinamicacid;

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamicacid;

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-2-methyl-phenyl]-malonamicacid; and

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-succinamicacid, or alkyl esters thereof, such as the methyl or ethyl ester.

The most preferred compounds of the invention are:

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid;and

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamicacid, or alkyl esters thereof, such as the methyl or ethyl ester.

Preferred compounds of formula IIA include trifluoro-methanesulfonicacid 2,6-dibromo-4-nitrophenyl ester, trifluoro-methanesulfonic acid2,6-dibromo-3-methyl-4-nitrophenyl ester, trifluoro-methanesulfonic acid2,6-dichloro-4-nitrophenyl ester, and trifluoro-methanesulfonic acid2,6-dichloro-3-methyl-4-nitrophenyl ester.

A more preferred compound of formula IIA is trifluoro-methanesulfonicacid 2,6-dibromo-4-nitrophenyl ester.

Preferred compounds of formula IIIA include1,3-dibromo-2-iodo-5-nitrobenzene,1,3-dibromo-2-iodo-4-methyl-5-nitrobenzene,1,3-dichloro-2-iodo-5-nitrobenzene, and1,3-dichloro-2-iodo-4-methyl-5-nitrobenzene.

A more preferred compound of formula IIIA is1,3-dibromo-2-iodo-5-nitrobenzene.

Preferred compounds of formulae A, A-I, and A-II for practicing thepresent invention are those in which R¹ represents halogen,trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl groupof 3 to 7 carbons.

More preferred compounds of formulae A, A-I, and A-II are those in whichR¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6carbons, or a cycloalkyl group of 3 to 7 carbons, most preferred beingisopropyl.

The most preferred compound of formula A-I is3-isopropyl-4-methoxybenzaldehyde. The most preferred compound offormula A-II is hydroxy-(3-isopropyl-4-methoxyphenyl)methanesulfonicacid, sodium salt. The most preferred phenol of formula A is3-isopropyl-4-methoxyphenol.

All stereoisomers of the compounds of formula I are contemplated, eitherin admixture or in pure or substantially pure form. The compounds offormula I can have asymmetric centers at any of the carbon atomsincluding any one of the R substituents. Consequently, compounds offormula I can exist in enantiomeric or diastereomeric forms or inmixtures thereof. The processes for preparation can utilize racemates,enantiomers or diastereomers as starting materials. When diastereomericor enantiomeric products are prepared, they can be separated byconventional methods, for example, chromatographic or fractionalcrystallization.

The compounds of formula I may be prepared by the exemplary processesdescribed in the following reaction schemes. Exemplary reagents andprocedures for these reactions appear hereinafter and in the workingexamples. Protection and deprotection in the Schemes herein may becarried out by procedures generally known in the art (see, for example,Greene & Wuts).

Scheme 1 sets forth an improved method of synthesizing compounds offormula I.

In scheme 1, R¹, R², R³, and R⁴ are as defined above, M represents ametal, the group G represents any group appropriate for protecting ahydroxyl moiety, and the group —OL represents a leaving group. Examplesof suitable protecting groups G can be found in Green and Wuts, forexample. Examples of suitable leaving groups L can be found in Carey, F.A. and Sundberg, R. J., Advanced Organic Chemistry (1977, Plenum Press,New York), Part A, Section 5.6, for example.

Preferred protecting groups include, e.g., substituted or unsubstitutedalkyl, methoxymethyl (MOM), carboxybenzyl (CBz), benzyloxymethyl (BOM),2-(trimethylsilyl) ethoxymethyl (SEM), aryl thiomethyl (MTM),tetrahydropyranyl, methyl 2-propenyl ether, ethyl vinyl ether,triphenylmethyl (trityl) and other triarylmethyl groups, esters,carbonates, phosphinates, sulfonates, and silyl groups.

More preferred protecting groups are alkyl groups.

The most preferred protecting groups are alkyl groups containing 1 to 6carbons, especially methyl groups.

Preferred leaving groups include, e.g., tri-haloacetates and sulfonateesters.

More preferred leaving groups are trihalo-methylsulfonate,methylsulfonate (mesyl), p-nitrobenzenesulfonate, p-toluenesulfonate(tosyl), and trihaloacetate groups.

The most preferred leaving groups are trifluoromethylsulfonate(triflate) groups.

Phenols of formula A may be synthesized by methods known in the art.See, for example, Blank, B., J. Med Chem., 1963, 6, 554, and Bowman etal., J. Chem. Soc. C, 1966, 2274. Phenols of formula A may also besynthesized by the novel method of the present invention, wherein analdehyde of formula A-I is reacted with about 2 to 4 equivalents of asulfite reagent, such as an sodium sulfite or an alkali hydrogensulfite, at about 20° to 30° C. to produce a sulfonate of formula A-II.Preferably, about 2.25 to 2.75 equivalents of sulfite reagent are used,the preferred sulfite reagent being sodium sulfite.

The phenol of formula A is formed by reacting the sulfonate of formulaA-II with an oxidant, in the presence of a proton source. Preferably,about 1 to 2 equivalents of protons and about 3 to 5 equivalents ofoxidant are used.

Suitable oxidants for use in the synthesis of Phenol A include, e.g.,peroxybenzoic acids, alkali metal monoperoxophthalates, hydrogenperoxide optionally catalyzed by Me—ReO₃, oxygen in the presence of acopper species, H₃PO₅, and oxone. More preferably, the oxidant ishydrogen peroxide.

Preferably, the proton source is a protic acid. More preferably, theproton source is p-toluenesulfonic acid.

Phenol B may be synthesized by well-known methods from commerciallyavailable starting materials. See, for example, Yenes, S. et al.,Tetrahedron, 1999, 55, 14111; Bozell, J. et al., Tet. Lett., 1998, 39,2261; Fischer, A. et al., Tet. Lett., 1988, 29, 1869; Rodygin, M. etal., Zh. Org. Khim., 1992, 28, 1926; Xu, F. et al., Shanghai Keji DaxueXuebao, 1989, 12, 72; Clewly, R. et al., Can. J. Chem., 1989, 67, 1472;Kajigaeshi, S. et al., Bull. Chem. Soc. Japan, 1987, 60, 4187;Kajigaeshi S. et al., Chem. Lett., 1987, 4, 627; Lemaire, M. et a.l,Tetrahedron, 1987, 43, 835; Fujita, S. et al., JP 03291241, 1991;Clewly, R. et al., Tetrahedron, 1989, 45, 1299; Kajigaeshi, S. et al.,Chem. Express, 1990, 5, 141; Kakinami, T. et al., Bull. Chem. Soc.Japan, 1989, 62, 3373; Kajigaeshi, S. et al., Technol. Rep. YamaguchiUniv., 1987, 4, 65; Gaude D. et al., Can. J. Chem., 1989, 67, 104;Kajigaeshi, S. et al., Chem. Lett., 1987, 2109. Certain Phenol Bcompounds are also commercially available from the Aldrich Company, forexample.

Compounds of formula III are synthesized from compounds of formula II byiodination. Iodination reagents include, e.g., alkali metal iodides andtetraalkylammonium iodides. Preferred iodination reagents include, e.g.,sodium iodide and potassium iodide. Preferably, the iodination agent ispresent in about 1-fold to 10-fold excess. Preferably, the iodination iscarried out at 80° to 110° C. Preferably, the solvent is acetone, methylethyl ketone (MEK), methyl isobutyl ketone (MIBK), toluene,hexamethylphosphorustriamide (HMPA), dimethyl formamide (DMF), or ahigher-boiling acetate. More preferably, the iodination is carried outby reacting the compound of formula II with 3- to 5-fold excess NaI orKI in DMF, MEK or MIBK at a temperature of about 75° to 100° C.

The coupling reaction to form the mixed ether of formula IV from thecompound of formula III and phenol A is conducted in the presence of abase. Preferred bases include, e.g., alkyl lithiums, lithiumdiisopropylamine, Grignard reagents, alkali metal hydrides, alkali metalcarbonates, alkali metal hydroxides, and alkali metal alkoxides.Preferred solvents include THF, 1,2-dimethoxyethane,1,1-dimethoxyethane, dimethyl sulfoxide (DMSO), and toluene. Preferably,about 1.1 to 1.5 equivalents of base are used. Preferably, the reactiontemperature is between about −78° and 30° C. More preferably, thecoupling reaction is performed in toluene/DMF or toluene/THF or DMF atroom temperature using potassium hexamethyldisilazide (KHMDS), potassiumt-butoxide, potassium t-pentoxide, LiHMDS, or NaHMDS as the base.

The deprotection of the protected hydroxyl group of compound IV may becarried out at reaction temperatures below room temperature. Preferreddeprotecting agents include, e.g., trialkylsilyl halides, mercaptans,boron halides, magnesium halides, aluminum halides, hydrogen overpalladium catalyst, or iron halides. Preferably, the reactiontemperature is maintained between about 0° to 15° C. Preferably, thedeprotection reaction is quenched with at least about 4 molarequivalents of methanol. More preferably, the deprotecting agent is atrialkylsilyl halide or BBr₃.

Reducing agents and conditions suitable for use in reducing the formulaV compound include, e.g., elemental metals such as Fe and Na; hydrogencatalyzed by nickel, palladium or platinum; alkali metal borohydrides;magnesium-mediated reductions; iron carbonyls; iron sulfate mediatedreductions; iron and HCl; sodium hydrogen sulfite; sodium dithionite;tin and tin halide mediated reductions; and alkali metal sulfides andpolysulfides. Preferred reducing agents include, e.g., sodium hydrogensulfite, sodium dithionite, or iron and HCl. Preferably, about 4 to 6equivalents of reducing agent are used. Preferably, the reactiontemperature is maintained between about 25° to 50° C. More preferably,the reducing agent is sodium dithionite, and the reaction is carried outover about 1 h in THF/H₂O at about 50° C.

Formula VI compounds may be converted into formula I compounds whereinR⁵ is an alkyl ester group by reaction with a compound of formulaXC(O)YR⁵, wherein X and Y are as defined above, under basic conditions.Preferred bases are alkali and alkaline earth metal hydroxides andalkoxides, alkyl amines, and substituted alkyl amines. Preferredcompounds of formula XC(O)YR⁵ are alkyl and malonyl halides. Preferably,the reaction temperature is maintained between about 0° and 5° C.Preferably, about 1 equivalent or a slight excess of base is used.Preferably, about 50% to 100% excess of the compound of formula XC(O)YR⁵is used. More preferably, XC(O)YR⁵ is ethyl or methyl malonyl chlorideand the reaction is carried out at a temperature around 0° C under basicconditions, using NaOH in t-butyl methyl ether (TBME).

In the above Scheme 1, the deprotection of the phenol hydroxyl group ofcompound IV to form the compound of formula V is depicted as beingperformed before the reduction of the nitro group to form the compoundof formula VI. The order in which these two reactions are performed maybe reversed, however. When the order is thus reversed, a compound offormula VA is formed by the reduction.

The compound of formula VA is readily deprotected to form the compoundof formula VI. It is preferred, however, to carry out the deprotectionbefore the reduction.

Compounds of formula I wherein R⁵ is an alkyl ester may be de-esterifiedby hydrolysis under acidic or basic conditions to form compounds offormula I wherein R⁵ is a carboxylic acid. Examples of suitablede-esterifying agents include, e.g., enzymes; hydrogen over catalyticpalladium; lithium and ammonia; zinc; alkali metal hydroxides andalkoxides; alkaline earth metal hydroxides and alkoxides; sodiumsulfide; KSCN; thioethers in combination with Lewis acids; anions ofalkyl thiols or selenols; trialkyl silyl halides; zinc dichloride;mercury (II) acetate; and strong protic acids.

Preferred hydrolysis reagents and conditions include, e.g., an alkalimetal hydroxide in the presence of an ether such as tetrahydrofuran ortert-butyl methyl ether. Most preferably, the hydrolysis is carried outin situ by the addition of approximately 1.5 to 2 molar equivalents ofNaOH to the reaction mixture at a temperature around 0° C. after thereaction of compound VI with XC(O)YR⁵ wherein X and Y are as previouslydefined and R⁵ is an alkyl ester group is observed to be essentiallycomplete.

The compounds made by the processes of the invention are agonists thatare preferably selective for the thyroid hormone receptor-beta, and assuch are useful in the treatment of obesity, hypercholesterolemia andatherosclerosis by lowering of serum LDL levels, alone or optionally incombination with a lipid modulating drug such as an HMG CoA reductaseinhibitor, fibrate, MTP inhibitor, squalene synthetase inhibitor and/orother hypolipidemic agent and/or optionally in combination with anantidiabetic agent; useful in the amelioration of depression, alone oroptionally in combination with an antidepressant such as fluoxetine anddesipramine; and useful in the stimulation of bone formation to treatosteoporosis, alone or optionally in combination with any known boneresorption inhibitor such as alendronate sodium.

In addition, the compounds of the invention may be useful as replacementtherapy in elderly patients with hypothyroidism or subclinicalhypothyroidism who are at risk for cardiovascular complications, in thetreatment of the elderly to provide a sense of well-being, and in thetreatment of non-toxic goiter; in the management of papillary orfollicular thyroid cancer (alone or with T4); in the treatment of skindisorders such as psoriasis; and in the treatment of glaucoma,cardiovascular disease such as in the prevention or treatment ofatherosclerosis, and congestive heart failure.

The compounds made by the processes of the invention may be employedalone or in combination with an appetite suppressant such assibutramine, and/or in combination with anti-obesity agents such asorlistat, and/or in combination with a β3 agonist, for treating obesity.

The compounds made by the processes of the invention may also be used totreat skin disorders or diseases involving dermal atrophy such asglucocorticoid induced dermal atrophy, including restoration of dermalatrophy induced by topical glucocorticoids, the prevention of dermalatrophy induced by topical glucocorticoids (such as the simultaneoustreatment with topical glucocorticoid or a pharmacological productincluding both glucocorticoid and a compound of the invention), therestoration/prevention of dermal atrophy induced by systemic treatmentwith glucocorticoids, restoration/prevention of atrophy in therespiratory system induced by local treatment with glucocorticoids,UV-induced dermal atrophy, or dermal atrophy induced by aging (wrinkles,etc.), wound healing, keloids, stria, cellulite, roughened skin, actinicskin damage, lichen planus, ichthyosis, acne, psoriasis, Dernier'sdisease, eczema, atopic dermatitis, chloracne, pityriasis and skinscarring.

In treating skin disorders or diseases as described above, the compoundsmade by the processes of the invention may be used alone or optionallyin combination with a retinoid such as tretinoin or a vitamin D analog,employing amounts as disclosed in the PDR.

The hypolipidemic agent which may be optionally employed in combinationwith the compounds of formula I may include thiazolidinediones, MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, cholesterolabsorption inhibitors, ileal Na⁺/bile acid cotransporter inhibitors,bile acid sequestrants, and/or nicotinic acid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279,U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No.5,885,983 and U.S. Pat. No. 5,962,440. Preferred are each of thepreferred MTP inhibitors disclosed in each of the above patents andapplications.

Most preferred MTP inhibitors to be employed with the compounds made bythe processes of the present invention include preferred MTP inhibitorsas set out in U.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No.5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide,formula VII.

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, pyrazole analogs ofmevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives as disclosed in PCTapplication WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0,142,146 A2, as well as other known HMGCoA reductase inhibitors.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use with compounds of formula I are disclosed inGB 2205837.

The squalene synthetase inhibitors suitable for use with compounds offormula I include, but are not limited to, α-phosphonosulfonatesdisclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al.,J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinylmethyl)phosphonates as well as other squalene synthetaseinhibitors as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and inBiller et al., Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for use withcompounds of formula I include the terpenoid pyrophosphates disclosed byP. Ortiz de Montellano et al., J. Med. Chem., 1977, 20, 243-249, thefarnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP)analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98,1291-1293, phosphinylphosphonates reported by McClard, R. W. et al,J.Am.Chem.Soc., 1987, 109, 5544 and cyclopropanes reported by Capson, T.L., PhD dissertation, June, 1987, Dept. Med. Chem. Univ. of Utah,Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use with compounds of formula Iinclude, but are not limited to, fibric acid derivatives, such asfenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,clinofibrate and the like, probucol, and related compounds as disclosedin U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred,bile acid sequestrants such as cholestyramine, colestipal andDEAE-Sephadex (Secholex™, Policexide™, as well as lipostabil(Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolaminederivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid, acipimox, acifran,neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine)derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternaryamine poly(diallyldimethylammonium chloride) and ionenes such asdisclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterollowering agents.

The other hypolipidemic agent may be an ACAT inhibitor such as disclosedin Drugs of the Future 24, 9-15 (1999), (Avasimibe); Nicolosi et al.,Atherosclerosis (Shannon, Ireland) 1998, 137(1), 77-85; Ghiselli,Giancarlo, Cardiovasc. Drug Rev. 1998, 16(1), 16-30; Smith, C., et al.,Bioorg. Med. Chem. Lett. 1996, 6(1), 47-50; Krause et al., Editor(s):Ruffolo et al., Inflammation: Mediators Pathways 1995, 173-98,Publisher: CRC Press, Boca Raton, Fla.; Sliskovic et al., Curr. Med.Chem. 1994, 1(3), 204-25; Stout et al., Chemtracts: Org. Chem. 1995,8(6), 359-62.

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin andcerivastatin.

The amounts and dosages employed will be as indicated in the Physician'sDesk Reference (PDR) and/or in the patents set out above.

The compounds of formula I will be employed in a weight ratio to thehypolypidemic agent, the antidepressant, and/or bone resorptioninhibitor and/or appetite suppressant (where present), within the rangefrom about 500:1 to about 0.005:1, preferably from about 300:1 to about0.01:1.

The antidiabetic agent which may be optionally employed in combinationwith compounds of formula I may include biguanides, sulfonyl ureas,glucosidase inhibitors, thiazolidinediones and/or aP2 inhibitors and/orPPAR α agonists, PPAR γ agonists or PPAR α/γ dual agonists, and/or SGLT2inhibitors, or meglitinide.

The antidiabetic agent may be an oral antihyperglycemic agent,preferably a biguanide such as metformin or phenformin or salts thereof.

Where the antidiabetic agent is a biguanide, the compounds of formula Iwill be employed in a weight ratio to biguanide within the range fromabout 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1.

The antidiabetic agent may also preferably be a sulfonylurea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the β-cells, with glyburide and glipizide beingpreferred.

The compounds of formula I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.2:1 to about 10:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in a separateoral dosage form.

The compounds of formula I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.5:1 to about 50:1.

The compounds of formula I may be employed in combination with athiazolidinedione oral anti-diabetic agent or other insulin sensitizers(which has an insulin sensitivity effect in NIDDM patients) such astroglitazone (Warner-Lambert's Rezulin™, disclosed in U.S. Pat. No.4,572,912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi'sMCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome'sGI-262570, englitazone (CP-68722, Pfizer), or darglitazone (CP-86325,Pfizer).

The compounds of formula I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.5:1 to about 5:1.

The sulfonylurea and thiazolidinedione in amounts of less than about 150mg oral antidiabetic agent may be incorporated in a single tablet withthe compounds of structure I.

The compounds of formula I may also be employed in combination with anon-oral antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, thedisclosure of which is incorporated herein by reference), which may beadministered via injection, intranasal, or by transdermal or buccaldevices.

Where present, metformin, the sulfonylureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin may be employedin formulations as described above and in amounts and dosing asindicated in the Physician's Desk Reference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day, whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physician's Desk Reference (PDR).

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224.

The antidiabetic agent may also be a PPAR α/γ dual agonist such asdisclosed by Murakami et al., “A Novel Insulin Sensitizer Acts As aColigand for Peroxisome Proliferation-Activated Receptor Alpha (PPARalpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal LipidMetabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998).

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and U.S.provisional application No. 60/127,745, filed Apr. 5, 1999, employingdosages as set out herein.

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. provisional application 60/158,773, filed Oct. 12, 1999.

The compounds of formula I will be employed in a weight ratio to thePPAR α agonist, PPAR γ agonist, PPAR α/γ dual agonists, SGLT2 inhibitorand/or aP2 inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.5:1 to about 5:1.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent andantidiabetic agent will be as disclosed in the various patents andapplications discussed above and in the Physicians' Desk Reference.

The dosages and formulations for the other hypolipidemic agent,antidepressant, bone resorption inhibitor, appetite suppressant andanti-obesity agent to be employed, where applicable, will be as set outin the latest edition of the Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg/kgto about 100 mg/kg and preferably from about 0.1 mg/kg to about 75mg/kg, one to four times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For parenteral administration, the MTP inhibitor will be employed in anamount within the range of from about 0.005 mg/kg to about 10 mg/kg andpreferably from about 0.005 mg/kg to about 8 mg/kg, one to four timesdaily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the Physician's Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 5 to about 80 mg, and more preferably fromabout 10 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The compounds of formula I and the hypolipidemic agent, antidepressantor bone resorption inhibitor may be employed together in the same oraldosage form or in separate oral dosage forms taken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin.

The compounds of formula I can be administered orally or parenterallysuch as subcutaneously or intravenously, as well as by nasalapplication, rectally or sublingually to various mammalian species knownto be subject to such maladies, e.g., humans, cats, dogs and the like inan effective amount within the dosage range of about 0.1 to about 100mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably fromabout 5 to about 2000 mg) on a regimen in single or 2 to 4 divided dailydoses.

The active substance can be utilized in a composition such as tablet,capsule, ointment, hydrophilic ointment, cream, lotion, solution orsuspension or in other type carrier materials such as transdermaldevices, iontophoretic devices, rectal suppositories, inhalant devicesand the like. The composition or carrier will contain about 5 to about500 mg per unit of dosage of a compound of formula I. The activesubstances may be compounded in a conventional matter with aphysiologically acceptable vehicle or carrier, excipient, binder,preservative, stabilizer, or flavor, as called for by acceptedpharmaceutical practice.

The following examples are provided to describe the invention in furtherdetail. These examples are intended to illustrate and not to limit theinvention. All temperatures are given in centigrade degrees (° C.)unless otherwise noted.

EXAMPLE 1 Preparation of 1-isopropyl-2-methoxybenzene

A 22 L three-necked round bottom flask equipped with mechanical stirringwas charged with KOH (1154 g, 20.56 moles), tetrabutylammonium hydrogensulfate (140 g, 0.411 mole), and deionized water (5.6 L). The mixturewas cooled to a temperature of approximately 20° C. to 25° C. Methylenechloride (5.6 L) was added to the flask, then 2-isopropylphenol (590 g,4.33 moles). The mixture was stirred for 0.5 h before iodomethane (741g, 5.22 moles) was added. The stirring was continued at room temperatureuntil the reaction was observed to be complete by HPLC, typically afterapproximately 5 h. Stirring was discontinued and the reaction mixturewas allowed to settle into aqueous and organic layers, which were thenseparated. Triethylamine (185 mL, 1.33 moles) was added to the organicphase with stirring for at least 15 min. Solvent was then removed byvacuum distillation to afford a white solid. Cyclohexane (41) was addedto the white solid, which was filtered and washed with furthercyclohexane to remove the reaction product as a solvate. The cyclohexanesolution was washed with aqueous HCl (2N), then half-saturated aqueousNaCl, and finally saturated aqueous NaCl. The cyclohexane was removed byvacuum distillation to afford 1-isopropyl-2-methoxybenzene as a lightyellow oil of medium viscosity (612 g, 94% yield).

EXAMPLE 2 Preparation of 3-isopropyl-4-methoxybenzaldehyde

A 5 L three-necked round bottom flask was equipped with mechanicalagitation and provided with an inert gas blanket. The flask was chargedwith 1-isopropyl-2-methoxybenzene (859 g, 5.85 moles) anddimethylformamide (1584 mL, 20.46 moles), and the mixture was heated to80° C. Phosphorus oxychloride (2690 g, 17.54 moles) was added to thereaction mixture over approximately 3 h while maintaining thetemperature of the reaction mixture between 80° C. and 90° C. Theaddition of POCl₃ caused an immediate color change with continuousdarkening over the course of the reaction. The reaction mixture wasmaintained at 80° C. for approximately 16 h, then checked by HPLC forpresence of unreacted starting materials. The reaction mixture wasquenched by slow addition over approximately 2 h to icewater (8 kgtotal, 5 kg ice); alternatively the reaction mixture was added overapproximately 3 h to deionized water (10 L) in a jacketed 30 L reactorwhose cooling bath was maintained between 0° and 5° C. Ethyl acetate (12L) was added to the quenched reaction with stirring. After settling, thelayers were separated, and the aqueous layer was washed with additionalethyl acetate (4 L). The combined organic layers were washed withsaturated aqueous sodium bicarbonate solution (4 L) and saturatedaqueous sodium chloride (4 L). The ethyl acetate was removed by vacuumdistillation to yield 3-isopropyl-4-methoxybenzaldehyde (881 g, 86.5%).

EXAMPLE 3 Preparation ofhydroxy-(3-isopropyl-4-methoxy-phenyl)methanesulfonic Acid, Sodium Salt

A 22 L three-necked round bottom flask equipped with mechanicalagitation was charged with 3-isopropyl-4-methoxybenzaldehyde (880 g,4.94 moles), THF (4650 mL), and cyclohexane (3740 mL) at roomtemperature. To this mixture was added, with stirring, an aqueoussolution of sodium bisulfite (1310 g, 12.56 moles, in 4360 mL ofdeionized water). The reaction mixture was stirred overnight at roomtemperature. The reaction product was removed by filtration, washedliberally with cyclohexane:THF (3:1) and dried overnight by evaporationunder air flow at room temperature to yieldhydroxy-(3-isopropyl-4-methoxyphenyl)methanesulfonic acid as the sodiumsalt (1302 g, 93.4%).

EXAMPLE 4 Preparation of 3-isopropyl-4-methoxyphenol

A 22 L three-necked round bottom flask equipped with mechanicalagitation was charged withhydroxy-(3-isopropyl-4-methoxyphenyl)methanesulfonic acid, sodium salt(1300 g, 4.61 moles), p-toluenesulfonic acid monohydrate (908 g, 4.77moles), and methanol (10.4 L), and the mixture was cooled to 0° to 5° C.Hydrogen peroxide (30% aqueous, 1.625 L, 16.12 moles) was added slowlyto the reaction mixture over about 2 h. The reaction mixture was stirredovernight and allowed to return to room temperature. The completeness ofthe reaction was assayed by HPLC; if the reaction was incomplete,further hydrogen peroxide was added to the reaction mixture. Thereaction mixture was cooled once more to 0° to 5° C. and then quenchedby addition of an aqueous slurry of sodium dithionite (1860 g, 10.68moles, stirred 1 h at room temperature in 6.5 L deionized water). Afterstirring at least 0.5 h, the reaction mixture was filtered, and thewhite solids were washed with ethyl acetate (8 L). The ethyl acetate andthe aqueous filtrate were combined, agitated, and allowed to separate.Cyclohexane was added if necessary to facilitate separation. The organicphase was washed with sodium bicarbonate (4 L, 10% aqueous solution),then with saturated aqueous sodium chloride solution (4 L). The solventwas removed by vacuum distillation to afford 3-isopropyl-4-methoxyphenol(510 g, 66.7%).

EXAMPLE 5 Preparation of Trifluoromethanesulfonic Acid2,6-dibromo-4-nitrophenyl Ester

A 12 L jacketed vessel equipped with a mechanical stirrer and nitrogeninlet adapter was charged with dichloromethane (3.2 L) and2,5-dibromo-4-nitrophenol (800 g, 2.69 moles). The reaction mixture wascooled to 0° C. and sparged with nitrogen gas. Pyridine (0.436 L, 3.23moles) was introduced via addition funnel while the temperature of thereaction mixture was maintained below 8° C. The reaction mixture wasstirred at 0° C. for 5 min, then a solution of triflic anhydride (0.544L, 3.23 moles) in dichloromethane (0.400 L) was added via additionfunnel while maintaining the reaction temperature below 10° C. Thereaction mixture was warmed to room temperature, stirred 30 min, andmonitored periodically by HPLC. After the reaction had run tocompletion, aqueous hydrochloric acid (1N, 1.6 L) was added to thereaction mixture dropwise with stirring. The reaction temperature wasmaintained below 35° C. during the addition of the acid. The reactionmixture was allowed to settle into layers, and the organic phase wasseparated and washed first with saturated aqueous sodium bicarbonate(0.8 L), then with saturated aqueous sodium chloride (0.8 L). Theorganic phase was concentrated by rotary evaporation under vacuum at 40°C., then dried overnight under vacuum to yield trifluoromethane sulfonicacid 2,6-dibromo-4-nitrophenyl ester (1140 g, 99.1%).

EXAMPLE 6 Preparation of 1,3-dibromo-2-iodo-5-nitrobenzene

Dimethylformamide (4 L) and trifluoromethane sulfonic acid2,6-dibromo-4-nitrophenyl ester (1135 g, 2.65 moles) were charged into a22 L jacketed vessel equipped with a mechanical stirrer, a condenser,and a nitrogen purge. Sodium iodide (1595 g, 10.64 moles) was added tothe reaction mixture in portions while maintaining the reactiontemperature below 25° C. The reaction mixture was then heated to 100° C.and monitored for completion by HPLC. Upon completion, the reactionmixture was cooled to 0° C. Water (4 L) was added while maintaining thetemperature below 14° C. The reaction mixture was stirred for 30 min,then filtered and washed with water (1.5 L). The resultant solid productwas dried overnight by evaporation under air flow at room temperature toyield 1,3-dibromo-2-iodo-5-nitrobenzene (892.7 g, 82.9%). The productmay optionally be purified further by recrystallization from ethanol.

EXAMPLE 7 Preparation of4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole

A 22 L jacketed vessel equipped with mechanical stirring and a nitrogeninlet adapter was charged with dimethylformamide (4 L) and3-isopropyl-4-methoxyphenol (462.8 g, 2.59 moles). The solution wascooled to 0° C., and KHMDS (5.50 L of 0.5M toluene solution, 2.25 moles)was added over 1.5 h while maintaining the temperature of the mixturebelow 2° C. The reaction mixture was stirred for 30 min at 2° C., then1,3-dibromo-2-iodo-5-nitro-benzene (798.6 g, 1.96 moles) was added inportions, still maintaining temperature of the mixture below 2° C. Afterthe addition was complete, the reaction mixture was allowed to stir atroom temperature for 2 h or until the reaction was complete as assayedby HPLC. The reaction mixture was cooled once more to 2° C. and ethylacetate (4.5 L) was added, followed by slow addition of saturatedaqueous sodium bicarbonate (6 L) while maintaining the temperature ofthe reaction mixture below 28° C. The organic layer was washed withsaturated aqueous sodium chloride solution, then concentrated by rotaryevaporation. The black, oily residue was taken up in acetone (3.87 L).Water (0.77 L) was added to the solution over 30 min with heating to 42°C. The solution was seeded with crystals of the product, cooled to 0°C., and stirred for 15 min. The resulting crystals of4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (665 g, 76.1%) wererecovered by filtration and dried for 48 h by evaporation under air flowat room temperature.

EXAMPLE 7A Preparation of4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole

3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved indimethylformamide (4 L). The mixture was stirred while the reactionvessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 1.0Maqueous solution, 1.278 moles) was added while maintaining thetemperature of the reaction mixture below 35° C.1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved indimethylformamide (portion of 4 L) was added to the reaction mixtureover approximately 45 min. The reaction mixture was stirred at 20° to25° C. for 24 h. Deionized water (2 L) was added over 2 h and thereaction mixture was cooled to 5° C. The resulting crystals of4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) wererecovered by filtration and dried for 48 h by evaporation under air flowat room temperature.

EXAMPLE 8 Preparation of4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylphenol

A 12 L three-necked round bottom flask equipped with a mechanicalstirrer, an addition funnel, and a temperature probe was charged with4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (752.1 g, 1.69 moles),which was dissolved by stirring in dichloromethane (2 L) at roomtemperature. The mixture was cooled to 8.7° C. in an ice-water bath. Asolution of boron tribromide (2.050 L, 1M in CH₂Cl₂, 2.05 moles) wasadded over 30 min. An increase of approximately 10° C. in thetemperature of the reaction mixture was observed. The ice-water bath wasremoved and the reaction mixture was allowed to stir at room temperatureuntil the reaction was complete, as assayed by HPLC. The reactionmixture was cooled once more in an ice-water bath, then quenched by slowaddition of methanol (850 mL), during which the temperature of thereaction mixture was maintained below 18° C. Saturated aqueous sodiumbicarbonate solution was added until the pH of the reaction mixture was6 or 7. The aqueous phase was separated and washed with aliquots ofethyl acetate (2×1 L). The organic layers were combined and the solventremoved under a vacuum at room temperature to yield crude4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylphenol (796 g, 110%).

EXAMPLE 9 Preparation of4-(4-amino-2,6-dibromophenoxy)-2-isopropylphenol

4-(2,6-Dibromo-4-nitrophenoxy)-2-isopropylphenol (795 g, 1.84 moles) wasdivided into three roughly equal portions. Each portion was dissolved inTHF (2.6 L) and charged into a 12 L three-necked round bottom flaskequipped with a mechanical stirrer, addition funnel, and temperatureprobe. The solutions were heated to 33° C. Sodium dithionite (482 g, 2.4moles) dissolved in deionized water (2.6 L) was added to each flask. Thereaction temperature was held at 50° C. until each reaction was completeas assayed by HPLC. Hydrochloric acid (6N aqueous) was added dropwise tothe heated reaction mixtures until their pH was about 3, and heating wascontinued for 45 min. The reaction mixtures were cooled to roomtemperature and their pH was adjusted to 6.6 by addition of saturatedaqueous sodium bicarbonate solution. Ethyl acetate (2.5 L) was added toeach flask with stirring for 2 min. Each reaction mixture was separated,and each organic layer was washed once with half-saturated aqueoussodium chloride solution, then once with saturated aqueous sodiumchloride solution. The solvents were removed by rotary evaporation andthe solids were dried overnight in a vacuum oven at 40° C. to yieldcrude 4-(4-amino-2,6-dibromophenoxy)-2-isopropylphenol (657 g, 96.9%).The crude 4-(4-amino-2,6-dibromophenoxy)-2-isopropylphenol was purifiedby recrystallization from isopropanol upon addition of 2.5 volumes ofdeionized water (90% recovery).

EXAMPLE 10 Preparation ofN-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenyl]malonamic Acid

A slurry of 4-(4-amino-2,6-dibromophenoxy)-2-isopropylphenol (160 g,0.401 mole) in t-butyl methyl ether (TBME, 1.07 L) was prepared in a 3L, three-necked round bottom flask equipped with a mechanical stirrer, athermocouple probe and an addition funnel. The mixture was cooled to 2°C. using a dry ice-acetone bath. A solution of sodium hydroxide (0.76M,0.53 L, 0.401 mole) was added over 20 min while keeping the internaltemperature of the reaction mixture below 2° C. Ethyl malonyl chloride(78.2 mL, 0.614 mole) was added via addition funnel to the biphasicmixture over 10 min while still maintaining the internal temperaturebelow 2° C. The cooling bath was removed and the mixture was stirred for40 min at room temperature. Fifteen minutes after the addition ofmalonyl chloride was completed, the reaction temperature was 5° C. andHPLC analysis of the reaction mixture failed to detect any remainingstarting material. The reaction mixture was once more cooled to 2° C.using a dry ice-acetone bath, and a solution of sodium hydroxide (10.0M, 176 mL, 1.76 moles) was added over 10 min. The internal temperatureof the reaction mixture was maintained below 2° C. After the additionwas complete, the cooling bath was removed and the mixture was stirredat room temperature. Two hours after the addition of NaOH was complete,the reaction temperature was 19° C. and none of the intermediate ethylester was detected by HPLC analysis. The organic layer was separated andextracted with water (150 mL). Any remaining traces of organic solventwere removed from the combined aqueous layers by distillation underreduced pressure. The aqueous solution was cooled in a dry ice-acetonebath to an internal temperature of 1° C. and acidified with HCl (10%aqueous, 1.25 L). The internal temperature of the mixture was maintainedbelow 2° C. throughout the addition. The resultant precipitated solidwas collected by filtration and washed twice with water. The solid wasdried to constant weight in a vacuum oven at 40° C. to provide crudeN-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)phenyl]malonamic acid asa beige solid (219.5 g, 113%). The crude product was recrystallized with90% recovery from methanol upon addition of water and cooling to 0° C.

COMPARATIVE EXAMPLE

Acetic anhydride (9.9 g, 97.5 mmoles) was charged to a three-neckedround bottom flask equipped with magnetic stirring, a nitrogen-inletadapter, and an addition funnel. The acetic anhydride was cooled to atemperature of 20° to 25° C. by immersing the flask in a dry ice-ethanolbath. Fuming nitric acid (6 g, 94.9 mmoles) was added dropwise to theacetic anhydride while maintaining the internal temperature of themixture. Iodine (ig, 3.94 mmoles) was added in one portion, followed bythe addition of trifluoroacetic anhydride (5.4 g, 47.3 mmoles). Thereaction mixture, which contained the unisolated intermediate iodoniumsalt (CF₃CO₂)₃ I, was warmed to room temperature.

An aliquot of the reaction mixture (9 mL) in a Reactive System ScreeningTool (RSST) was placed inside a bomb. The bomb was pressurized withnitrogen (300 psig at 15° C.) and heated at the rate of 1° C./min. The10 mL glass cell of the RSST did not break; however, some of thereaction mixture erupted into the bomb, and the remainder of the aliquotchanged color from red to dark purple-black.

FIG. 1 is a graph of the resulting temperature vs. time measurements. Itis apparent that an exothermic reaction began almost immediately withthe commencement of heating. Similar results were obtained indifferential scanning calorimetry (DSC) experiments. The data in FIG. 1,and the accompanying observations, illustrate that the thermaldecomposition of the unisolated iodonium salt (CF₃CO₂)3 I is so highlyexothermic as to render (CF₃CO₂)3 I hazardous as an intermediate inlarge scale preparations.

2-Isopropylphenol was reacted with methyl iodide in the presence ofpotassium carbonate to yield 1-isopropyl-2-methoxybenzene, which in turnwas reacted with the solution of unisolated intermediate (CF₃CO₂)₃ Idescribed above to form the bis-[3-isopropyl-4-methoxyphenyl] iodoniumsalt in 40-70% yield. The bis-[3-isopropyl-4-methoxyphenyl] iodoniumsalt precipitated as a gummy solid, making purification impracticableand contributing to the unpredictability of the yield.

The bis-[3-isopropyl-4-methoxyphenyl] iodonium salt was reacted with2,6-dibromo-4-nitrophenol in the presence of elemental copper andtriethylamine, over the course of 4 to 5 days in the dark, to form4-(4-nitro-2,6-dibromophenoxy)-2-isopropylphenol in 50 to 80% yield. Theextended time required for the ether formation, its unpredictable yield,and the unusual necessity to exclude light are inefficiencies that alsomilitate against commercial practice of this synthetic route.

The entire disclosures of the patents and other publications cited aboveare incorporated herein by reference. While certain preferredembodiments of the present invention have been described andspecifically exemplified above, it is not intended that the invention belimited to such embodiments. Various modifications may be made to theinvention without departing from the scope and spirit thereof as setforth in the following claims.

What is claimed is:
 1. A process for synthesizing a compound of formulaI

wherein R¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6carbons, or a cycloalkyl group of 3 to 7 carbons; R² and R⁵ are the sameor different and represent hydrogen, halogen, an alkyl group of 1 to 4carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R² andR³ being other than, hydrogen; R⁴ represents hydrogen or a lower alkylgroup; R⁵ represents a carboxylic acid or an alkyl ester thereof; and Yrepresents —(CH₂)_(n)—where n is an integer from 1 to 5, or a cis- ortrans-ethylene group —CH=CH—; and all stereoisomers thereof; saidprocess comprising the steps of: a) reacting a compound of formula IIIwith a phenol of formula A, wherein R¹, R², R³, and R⁴ are as definedabove and G is a protecting group, in the presence of a base to producea compound of formula IV;

b) deprotecting and reducing the compound of formula IV to form acompound of formula VI;

c) reacting the compound of formula VI with a compound of the formulaXC(O)YR⁵, wherein X represents OH or a halogen and R⁵ is a carboxylicacid alkyl ester, in the presence of a base, to produce a compound offormula I wherein R⁵ is a carboxylic acid alkyl ester; and (d)optionally de-esterifying the compound of formula I wherein R⁵ is acarboxylic acid alkyl ester to produce a compound of formula I whereinR⁵ is a carboxylic acid; wherein the compound of Formula III is producedby reacting a compound of formula II

wherein L is a leaving group; R² and R³ are the same or different andrepresent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or acycloalkyl group of 3 to 6 carbons, at least one of R² and R³ beingother than hydrogen; and R⁴ alkyl group; with an iodinating agent. 2.The process of claim 1, wherein, in step a, the base is selected fromthe group consisting of potassium hexamethyldisilazide (KHMDS), lithiumhexamethyldisilazide, sodium hexamethyldisilazide, alkyl lithiums,lithium diisopropylamine, Grignard reagents, alkali metal hydrides,alkali metal carbonates, alkali metal hydroxides, and alkali metalalkoxides.
 3. The process of claim 2, wherein, in step a, the base isselected from the group consisting of potassium hexamethyldisilazide(KHMDS), potassium t-butoxide, potassium t-pentoxide, LiHMDS, or NaHMDS.4. The process of claim 3, wherein, in step a, the base is potassiumhexamethyldisilazide.
 5. The process of claim 1, wherein, in step b, thedeprotecting agent is selected from the group consisting oftrialkylsilyl halides, mercaptans, boron halides, magnesium halides,alumnum halides, hydrogen over palladium catalyst, or iron halides. 6.The process of claim 5, wherein, in step b, the deprotecting agent is atrialkylsilyl halide or BBr₃.
 7. The process of claim 6, wherein, instep b, the compound of formula IV is deprotected by reaction with BBr₃.8. The process of claim 1, wherein, in step b, the reducing agent isselected from the group consisting of elemental metals; hydrogencatalyzed by nickel, palladium or platinum; alkali metal borohydrides;magnesium-mediated, reductions; iron carbonyls; iron sulfate mediatedreductions; iron and HCl; sodium hydrogen sulfite; sodium dithionite;tin and tin halide mediated reductions; and alkali metal sulfides endpolysulfides.
 9. The process of claim 8, wherein, in step b, thereducing agent is selected from the group consisting of sodium hydrogensulfite; sodium dithionite; and iron and HCl.
 10. The process of claim9, wherein, in step b, the reducing agent is sodium dithionite.
 11. Theprocess of claim 1, wherein, in step c, the base is selected from thegroup consisting of alkali metal hydroxides and alkoxides; alkalineearth metal hydroxides and alkoxides; alkyl amines; and substitutedalkyl amines.
 12. The process of claim 11, wherein, in step c, the baseis selected from the group consisting of alkali metal hydroxides andalkaline earth metal hydroxides.
 13. The process of claim 12, wherein,in step c, the base is sodium hydroxide.
 14. The process of claim 1,wherein, in step d, the de-esterifying agent is selected from the groupconsisting of enzymes; hydrogen ever catalytic palladium; lithium andammonia; zinc; alkali metal hydroxides and alkoxides; alkaline earthmetal hydroxides and alkoxides; sodium sulfide; KSCN; thioethers incombination with Lewis acids; anions of alkyl thiols or selenols;trialkyl silyl halides; zinc dichloride; mercury (II) acetate; andstrong protic acids.
 15. The process of claim 14, wherein, in step d,the de-esterifying agent is an alkali metal hydroxide.
 16. The processof claim 15, wherein, in step d, the de-esterifying agent is sodiumhydroxide.
 17. The process of claim 1, wherein the iodinating agent isselected from the group consisting of alkali metal iodides andtetraalkylammonium, iodides.
 18. The process of claim 17, wherein theiodinating agent is selected from the group consisting of sodium iodideand potassium iodide.
 19. The process of claim 17, wherein theiodinating agent is sodium iodide.
 20. The process of claim 1 whereinthe compound of formula IV is first deprotected to form a compound offormula V

and then reduced to form the compound of formula VI wherein thevariables R1-R4 are defined as in claim
 1. 21. The process of claim 1wherein the compound of formula IV is first reduced to form a compoundof formula VA

and then deprotected to form the compound of formula VI wherein thevariables R1-R4 and G are defined as in claim
 1. 22. The process ofclaim 1 for the preparation of a formula I compound wherein Y represents—(CH₂)_(n)— where n is 1 or 2; R¹ represents halogen, trifluorormethyl,an alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 7carbons; R² and R³ independently represent bromo, chloro, or methyl; R⁴represents hydrogen or methyl; and R⁵ represents carboxyl.
 23. Theprocess of claim 1 for the preparation of a formula I compound wherein Yrepresents —(CH₂)_(n)— where n is 1; R¹ represents halogen,trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl,group of 3 to 7 carbons; R² and R² independently represent bromo orchloro; R⁴ represents hydrogen or methyl; and R⁵ represents carboxyl.24. The process of claim 1 wherein the compound of formula I is selectedfrom the group consisting of

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-2-methyl—phenyl]-malonamicacid;

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-succinamicacid;

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamicacid;

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-2-methyl-phenyl]-malonamicacid; and

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-2-phenyl]-succinamicacid, and alkyl esters thereof.
 25. The process of claim 1 wherein thecompound of formula I is

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid,or

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamicacid, and alkyl esters thereof.
 26. The process of claim 1 wherein thecompound of formula I is

and alkyl esters thereof.